ABSTRACT Down syndrome (DS) is the most common genetic cause of intellectual disability and a huge biomedical problem of increasing concern. Currently, there are no treatments that can prevent, delay, or restore deficits in learning and memory associated with DS. Thus, the identification of novel neuronal targets for the development of pharmacotherapies to treat memory decline associated with DS is an important goal. It has been hypothesized that alterations in protein synthesis (mRNA translation) could contribute to the molecular, synaptic, and behavioral abnormalities of neurodevelopmental disorders, but whether dysfunctional protein synthesis is responsible for the DS pathology remains unknown. The goal of this competing renewal is to identify and correct the aberrant translational control program underlying DS pathophysiology. We focus on protein synthesis controlled by the PKR-eIF2? signaling pathway because a) our preliminary findings indicate that PKR-eIF2? signaling is selectively perturbed in the DS brain, and b) during the previous funding period, we discovered PKR-eIF2? signaling as a central mechanism regulating not only the formation of long-term memory, but also the two major and opposing forms of synaptic plasticity in the brain. We will combine genetics, state-of-the-art intersectional molecular genetic approaches, pharmacology, electrophysiology, cell- type-specific manipulation, genomics, and behavior to define the translational and synaptic plasticity mechanisms underlying cognitive deficits in Down syndrome. We anticipate that the results of these Aims will provide new fundamental insights into the biological basis of intellectual disability and could open avenues for new therapies.